Impact of bile salts and a medium chain fatty acid on the physical properties of self-emulsifying drug delivery systems

Figures & data

Table 1. Composition (w/w %) of nonionic formulations.

F1
Peceol	30%	Lupo et al. [21]
Tween 80	50%
Propylene Glycol	10%
DMSO	10%
F2
Miglyol 840	40%	Leichner et al. [22]
Tween 80	40%
Glycerol 85%	10%
Ethanol	10%
F3
Capmul PG8	25%
Labrafil M 1944 CS	35%
Cremophor EL	40%
Propylene Glycol	10%
F4
Ethyl Oleate	30%
Capmul MCM	30%
Cremophor EL	30%
Cremophor RH	10%
F5
Peceol	10%	Zupančič et al. [5]
Capmul PG8	20%
Cremophor EL	60%
Transcutol	10%

Table 2. Composition (w/w %) of cationic SEDDS.

F6 (3% DDAC)
DODAB	3%
Peceol	27%
Tween 80	50%
Propylene Glycol	10%
DMSO	10%
F7 (3% DDAC)
DODAB	3%
Captex 355	47%
Tween 80	40%
Ethanol	10%
F8 (3% PPTC)
PPTC	3%
Miglyol 840	37%
Tween 80	40%
Glycerol 85%	10%
Ethanol	10%
F9 (6% DDAC)
DODAB	6%
Capmul MCM	17%
Captex 355	17%
Tween 80	50%
Glycerol 85%	10%
F10 (6% PPTC)
PPTC	6%
Ethyl Oleate	44%
Tween 80	40%
Ethanol	10%

Table 3. Chemical structure of cationic surfactants incorporated in SEDDS.

Chemical name	Structure	Chain length
Dioctadecyldimethylammonium chloride (DODAB)		C38
Palmitamidopropyltrimonium chloride (PPTC)		C22

Figure 1. (A–D) Zeta potential (mV) of nonionic (A) and cationic (B) SEDDS (0.5% m/v) emulsified in water containing indicated concentrations of bile salts; Zeta potential of nonionic (C) and cationic (D) SEDDS (0.5% m/v) emulsified in water containing indicated concentrations of sodium decanoate. Indicated values are means ± SD (n = 3). (Two way ANOVA vs water, * p < 0.05, ** p < 0.01, *** p < 0.001).

Figure 2. (A–D) Size (nm) of nonionic (A) and cationic (B) SEDDS (0.5% m/v) emulsified in water containing indicated concentrations of bile salts; Size (nm) of nonionic (C) and cationic (D) SEDDS (0.5% m/v) emulsified in water containing indicated concentrations of sodium decanoate. Indicated values are means ± SD (n = 3). (Two way ANOVA vs water, * p < 0.05, ** p < 0.01, *** p < 0.001).

Figure 3. (A –D) PDI of nonionic (A) and cationic (B) SEDDS (0.5% m/v) emulsified in water containing indicated concentrations of bile salts; PDI of nonionic (C) and cationic (D) SEDDS (0.5% m/v) emulsified in water containing indicated concentrations of sodium decanoate. Indicated values are means ± SD (n = 3). (Two way ANOVA vs water, * p < 0.05, ** p < 0.01, *** p < 0.001).

Figure 4. (A ,B) Size distribution of formulation F5 emulsified in water and water containing 5 mM (BS 5 mM) and 15 mM (BS 15 mM) bile salts (A); Size distribution of formulation F5 emulsified in water and water containing 5 mM (Dec 5 mM) and 15 mM (Dec 15 mM) sodium decanoate (B).

Figure 5. (A–D): Transmittance % of nonionic (A) and cationic (B) SEDDS (0.5% m/v) emulsified in water containing indicated concentrations of bile salts; Transmittance % of nonionic (C) and cationic (D) SEDDS (0.5% m/v) emulsified in water containing indicated concentrations of sodium decanoate. Indicated values are means ± SD (n = 3). (Two way ANOVA vs water, * p < 0.05, ** p < 0.01, *** p < 0.001).

Figure 6. (A–D) Cloud point temperature (CPT) of nonionic (A) and cationic (B) SEDDS (0.5% m/v) emulsified in water containing indicated concentrations of bile salts; (CPT) of nonionic (C) and cationic (D) SEDDS (0.5% m/v) emulsified in water containing indicated concentrations of sodium decanoate. Indicated values are means ± SD (n = 3). (Two way ANOVA vs water, * p < 0.05, ** p < 0.01, *** p < 0.001. In case of formulations having a cloud point temperature above 100 °C, (CPT) was not experimentally determined, therefore statistical analysis was performed assuming a (CPT) equal to 100 °C).

Figure 7. Release of quinine from ni-SEDDS (F1, F2, F3, F4 and F5) and c-SEDDS (F6, F7, F8, F9, F10) at time points 15,60,120,180,240 min in water (w) and BS (15 mM) and dec (25 mM) containing medium (b).

Table A1. Zeta potential (mV) of nonionic (ni-SEDDS) and cationic (c-SEDDS) SEDDS (0.5% m/v) emulsified in water containing indicated concentrations of bile salts or decanoate; Indicated values are means ± SD (n = 3).

	water	BS 1.5 mM	BS 5 mM	BS 9 mM	BS 15 mM
Bile salts
Ni-SEDDS
F1	–7.8 ± 3	–17.8 ± 0.4	–24.7 ± 0.7	–33.3 ± 1.3	–29.9 ± 0.8
F2	–2.7 ± 0.5	–13.9 ± 0.4	–18.9 ± 1	–26.2 ± 1	–23.8 ± 1
F3	–5.7 ± 3	–8.6 ± 0.7	–12.6 ± 2	–16 ± 1.73	–14.7 ± 2
F4	–3.2 ± 2.1	–8.2 ± 0.7	–14.4 ± 1.3	–16.8 ± 3.4	–19.8 ± 0.8
F5	–4 ± 2.4	–14.9 ± 0.7	–19.7 ± 0.9	–11.8 ± 1	–12.7 ± 1.5
c-SEDDS
F6	19.3 ± 0.6	–9 ± 0.2	–18.2 ± 0.4	–32.9 ± 1.7	–29.7 ± 2.3
F7	16.8 ± 0.7	–7.8 ± 0.3	–18.7 ± 0.4	–28.4 ± 0.5	–28.8 ± 1.6
F8	22.4 ± 0.8	–5.3 ± 0.2	–15.1 ± 0.2	–25.9 ± 0.8	–26.1 ± 1.8
F9	28.7 ± 1.2	1.2 ± 2.1	–17.9 ± 0.1	–32.5 ± 0.8	–28.4 ± 0.4
F10	23.7 ± 2.8	3.7 ± 0.2	–8.7 ± 0.5	–23.4 ± 1.2	–25.5 ± 2.1
	water	Dec 0.1 mM	Dec 0.5 mM	Dec 5 mM	Dec 15 mM	Dec 25 mM
Decanoate
Ni-SEDDS
F1	–7.8 ± 3	–6.2 ± 0.8	–11.9 ± 1.1	–18.7 ± 0.9	–23.9 ± 1.6	–23.5 ± 1.7
F2	–2.7 ± 0.5	–3.9 ± 0.3	–7 ± 0.4	–10.8 ± 1.4	–19.7 ± 1	–17.4 ± 1.9
F3	–5.7 ± 3	–3.6 ± 0.7	–7.5 ± 0.1	–5.9 ± 2.1	–15.9 ± 0.6	–15.9 ± 1.6
F4	–3.2 ± 2.1	–2.4 ± 0.3	–5.7 ± 0.7	–6.2 ± 0.5	–14.1 ± 0.8	–14 ± 1.6
F5	–4 ± 2.4	–3 ± 0.2	–7.2 ± 0.3	–13 ± 0.7	–20.5 ± 1.3	–17.4 ± 1.8
c-SEDDS
F6	19.3 ± 0.6	8.6 ± 0.2	–1.8 ± 0.01	–13.9 ± 0.7	–22.4 ± 1.6	–18.5 ± 0.6
F7	16.8 ± 0.7	13.8 ± 0.9	4.3 ± 0.48	–8.9 ± 0.6	–17.1 ± 2.2	–16.1 ± 2.5
F8	22.4 ± 0.8	16.3 ± 1.2	7.0 ± 0.83	–5.4 ± 0.2	–17.8 ± 2.5	–19 ± 2.3
F9	28.7 ± 1.2	20.9 ± 1.0	10.5 ± 0.74	–10.7 ± 0.3	–21.8 ± 3.3	–15.9 ± 2.7
F10	23.7 ± 2.8	16.6 ± 1.7	10.6 ± 1.15	–2.4 ± 0.4	–13.1 ± 1.6	–12.9 ± 1.5

Table A2. Size (nm) of nonionic (ni-SEDDS) and cationic (c-SEDDS) SEDDS (0.5% m/v) emulsified in water containing indicated concentrations of bile salts or decanoate; Indicated values are means ± SD (n = 3). Formulations not significantly affected by bile salts or decanoate are not reported in the table.

	water	BS 1.5 mM	BS 5 mM	BS 9 mM	BS 15 mM
Bile salts
Ni-SEDDS
F1	226.6 ± 10.4	189.2 ± 2.7	165.4 ± 1.2	119.7 ± 3.4	114.9 ± 5.3
F5	157.9 ± 4.3	101.4 ± 0.3	71.4 ± 0.7	12.5 ± 0.2	13.2 ± 0.1
c-SEDDS
F6	168.3 ± 7.91	150.1 ± 2	129.2 ± 1.3	115.2 ± 3	115.3 ± 1.9
	water	Dec 0.1 mM	Dec 0.5 mM	Dec 5 mM	Dec 15 mM	Dec 25 mM
Decanoate
Ni-SEDDS
F1	226.6 ± 10.4	233.2 ± 9	195.3 ± 3.6	193.3 ± 1.3	149.9 ± 3.6	161.2 ± 14
F5	157.9 ± 4.3	114.9 ± 6.7	110.0 ± 6.9	102.9 ± 6.6	37.1 ± 3.9	45.1 ± 1.6

Table A3. PDI of nonionic (ni-SEDDS) and cationic (c-SEDDS) SEDDS (0.5% m/v) emulsified in water containing indicated concentrations of bile salts or decanoate; Indicated values are means ± SD (n = 3). Formulations not significantly affected by bile salts or decanoate are not reported in the table.

	water	BS 1.5 mM	BS 5 mM	BS 9 mM	BS 15 mM
Bile salts
Ni-SEDDS
F1	0.46 ± 0.03	0.3 ± 0.029	0.33 ± 0.060	0.29 ± 0.006	0.29 ± 0.009
F2	0.21 ± 0.010	0.18 ± 0.01	0.18 ± 0.009	0.18 ± 0.019	0.15 ± 0.01
F3	0.06 ± 0.018	0.03 ± 0.005	0.05 ± 0.009	0.05 ± 0.011	0.06 ± 0.001
F4	0.11 ± 0.013	0.07 ± 0.009	0.04 ± 0.008	0.05 ± 0.009	0.06 ± 0.005
F5	0.3 ± 0.004	0.27 ± 0.008	0.6 ± 0.011	0.11 ± 0.011	0.09 ± 0.001
c-SEDDS
F6	0.45 ± 0.022	0.44 ± 0.004	0.3 ± 0.006	0.28 ± 0.008	0.3 ± 0.005
F9	0.42 ± 0.06	0.33 ± 0.04	0.35 ± 0.04	0.28 ± 0.02	0.3 ± 0.02
	water	Dec 0.1 mM	Dec 0.5 mM	Dec 5 mM	Dec 15 mM	Dec 25 mM
Decanoate
Ni-SEDDS
F1	0.46 ± 0.03	0.48 ± 0.02	0.43 ± 0.01	0.43 ± 0.01	0.34 ± 0.05	0.33 ± 0.05
F5	0.3 ± 0.004	0.27 ± 0.011	0.3 ± 0.003	0.48 ± 0.031	0.46 ± 0.005	0.8 ± 0.048
c-SEDDS
F6	0.45 ± 0.022	0.46 ± 0.004	0.44 ± 0.021	0.42 ± 0.024	0.37 ± 0.045	0.32 ± 0.051
F7	0.31 ± 0.004	0.25 ± 0.003	0.26 ± 0.008	0.22 ± 0.005	0.21 ± 0.010	0.22 ± 0.009
F9	0.42 ± 0.06	0.47 ± 0.010	0.39 ± 0.024	0.42 ± 0.021	0.35 ± 0.038	0.27 ± 0.040
F10	0.25 ± 0.0012	0.2 ± 0.015	0.22 ± 0.026	0.2 ± 0.012	0.21 ± 0.042	0.19 ± 0.011

Table A4. Transmittance (%) of nonionic (ni-SEDDS) and cationic (c-SEDDS) SEDDS (0.5% m/v) emulsified in water containing indicated concentrations of bile salts or decanoate; Indicated values are means ± SD (n = 3). Formulations not significantly affected by bile salts or decanoate are not reported in the table.

	water	BS 1.5 mM	BS 5 mM	BS 9 mM	BS 15 mM
Bile salts
Ni-SEDDS
F1	6.1 ± 0.2	15.6 ± 1.3	18.9 ± 2.4	49.7 ± 1.8	47.0 ± 2.7
F2	73.7 ± 1.2	73.2 ± 2.4	78.9 ± 1.5	80.2 ± 2.3	80.4 ± 2.8
F5	75.1 ± 2.1	96.5 ± 0.3	97.0 ± 0.4	100.0 ± 0.0	100.0 ± 0.0
c-SEDDS
F6	37.0 ± 4.4	58.6 ± 1.8	65.3 ± 3.3	85.8 ± 0.9	88.6 ± 1.5
F9	45.6 ± 1.5	66.1 ± 1.4	60.2 ± 4.2	69.8 ± 7.0	70.5 ± 3.7
F10	87.7 ± 4.6	89.4 ± 1.3	87.6 ± 2.4	91.6 ± 1.2	90.6 ± 1.7
	water	Dec 0.1 mM	Dec 0.5 mM	Dec 5 mM	Dec 15 mM	Dec 25 mM
Decanoate
Ni-SEDDS
F1	6.1 ± 0.2	6.9 ± 0.6	15.6 ± 0.7	16.4 ± 1.0	51.8 ± 1.9	53.0 ± 1.4
F5	75.1 ± 2.1	76.7 ± 0.6	85.5 ± 1.3	91.7 ± 1.3	94.6 ± 0.6	96.2 ± 0.9
c-SEDDS
F6	37.0 ± 4.4	38.6 ± 1.7	43.0 ± 1.2	44.6 ± 0.7	49.9 ± 5.3	66.6 ± 1.9
F7	62.5 ± 8.4	66.8 ± 7.0	67.9 ± 2.3	70.3 ± 1.2	74.5 ± 2.3	73.8 ± 1.2
F9	45.6 ± 1.5	47.2 ± 2.3	49.0 ± 1.3	53.5 ± 2.8	55.9 ± 1.5	60.0 ± 1.5
F10	87.7 ± 4.6	93.0 ± 1.4	95.0 ± 1.3	95.8 ± 0.9	94.1 ± 1.6	96.3 ± 0.8

Table A5. Cloud point temperature (°C) of nonionic (ni-SEDDS) and cationic (c-SEDDS) SEDDS (0.5% m/v) emulsified in water containing indicated concentrations of bile salts or decanoate; Indicated values are means ± SD (n = 3). Formulations not significantly affected by bile salts or decanoate are not reported in the table.

	water	BS 1.5 mM	BS 5 mM	BS 9 mM	BS 15 mM
Bile salts
Ni-SEDDS
F1	70.7 ± 3	86.7 ± 1.2	90 ± 1.5	94.7 ± 1.5	97.3 ± 1.5
F3	58.0 ± 2	74.0 ± 1.1	91.3 ± 3	96 ± 2	97.7 ± 0.6
F4	60 ± 2	80.7 ± 3	88.7 ± 3	93.3 ± 1.5	98.7 ± 1.5
F5	59.3 ± 3	72.0 ± 2	76.7 ± 1.15	86.0 ± 2	94.7 ± 1.15
c-SEDDS
F6	110.0	79.3 ± 3.1	90.0 ± 2.0	92 ± 2	99 ± 1
F7	110.0	92.7 ± 1.2	96.67 ± 0.6	98.0 ± 0	99.3 ± 1.5
F8	110.0	92.7 ± 1.2	54.7 ± 4.2	62.3 ± 2	76 ± 2
F9	110.0	93.0 ± 1.7	78.0 ± 2.0	82.0 ± 2	86.0 ± 2
F10	110.0	90.7 ± 1.2	93.3 ± 1.2	98.67 ± 1.15	110.0
	water	Dec 0.1 mM	Dec 0.5 mM	Dec 5 mM	Dec 15 mM	Dec 25 mM
Decanoate
Ni-SEDDS
F1	70.67 ± 3	70 ± 2	76 ± 1	78.33 ± 1.5	84 ± 1	90.67 ± 1.15
F3	58.0 ± 2	60.33 ± 1.5	62.33 ± 2.5	68 ± 1	74 ± 1	76 ± 1
F4	60 ± 2	62 ± 1	63.33 ± 1.52	71.67 ± 1.5	76.67 ± 0.6	82 ± 1.73
F5	59.33 ± 3	61 ± 1	62.67 ± 0.6	68.33 ± 0.6	74.67 ± 1.15	80 ± 2
c-SEDDS
F6	110	97.0 ± 1	94.3 ± 1.15	87 ± 1	98.67 ± 1.15	110
F7	110	110.0	96 ± 1	93.67 ± 1.15	97.67 ± 0.6	110
F8	110	110.0	96.3 ± 1.52	83 ± 1.73	97.67 ± 0.6	110
F9	110	97.3 ± 1.2	94.67 ± 1.15	86.3 ± 1.52	90 ± 2	110
F10	110	97.0 ± 1.0	96.3 ± 0.6	94 ± 1	110	110

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